Cyclohexane derivatives

ABSTRACT

This invention concerns compounds of generic formula: ##STR1## or a pharmaceutically acceptable salt thereof, where the dotted line represents an optional bond, 
     one of R 1  and R 5  represents hydrogen, C 1  -C 6  alkyl, C 7  -C 16  aralkyl, --(CHR 6 ) n  CHR 7  CN, --(CHR 6 ) n  CHR 7  CONH 2 , --(CHR 6 ) n  CHR 7  COOR 8 , --(CHR 6 ) n  CHR 7  CH 2  OH wherein n is 0 or 1, R 6  and R 7  independently represent hydrogen, C 1  -C 6  alkyl- or C 7  -C 16  aralkyl-, and R 7  also represents hydroxy(C 1  -C 6 )alkyl-, (C 2  -C 7 )alkanoyloxy(C 1  -C 6 )alkyl-, (C 1  -C 6  alkoxy)carbonyl- and R 8  is hydrogen or C 1  -C 6  alkyl; 
     the other of R 1  and R 5  is hydrogen, C 1  -C 6  alkyl or C 7  -C 16  aralkyl; R 3  is C 6  -C 10  aryl or heteroaryl group optionally substituted by one or more substituents the same or differnet, 
     R 2  and R 4  independently represent hydrogen, or a group of formula --CR a  R b  R c  where R a , R b  and R c  are independently selected from hydrogen, C 1  -C 6  alkyl, optionally substituted C 6  -C 10  aryl, optionally substituted heteroaryl, C 1  -C 6  alkyl substituted by optionally substituted C 6  -C 10  aryl or heteroaryl or R 2  also represents COR 11  where R 11  is C 1  -C 6  alkyl, C 1  -C 6  alkoxy or an optionally substituted (C 6  -C 10  aryl)alkyl or a heteroaryl alkyl radical; one of Y and Y 1  is ##STR2## where R 13  represents hydrogen, C 1  -C 6  alkyl or C 7  -C 16  aralkyl; the other of Y and Y 1  is --CHR 12  -- where R 12  is hydrogen, C 1  -C 6  alkyl or C 7  -C 16  aralkyl, 
     which compounds have pharmaceutical uses conferred by their ability to block voltage gated potassium channels.

This invention relates to cyclohexane derivatives more particularly tosubstituted aminocyclohexanes, to processes for preparing them topharmaceutical compositions containing them. The compounds havepharmaceutical uses conferred by their ability to block voltage gatedpotassium channels and they are also useful as intermediates to nitrogenheterocycles which are potassium channel blockers.

Voltage gated potassium ion (K⁺) channels which produce transientoutward currents (TOC) are present in the cell membranes of neurones andserve to repolarise the cell following a depolarisation by opening andallowing potassium ions to flow from the inside of the cell to theoutside. They are, therefore, one of the main regulating influences onthe nerve cell firing and determine the amount of current reaching theterminal regions of the cells. This in turn regulates the amount ofneurotransmitter substances released from the nerve terminals. Inaddition, they help to determine the refractory period of the nerve celland hence the probability of the cell firing again within a certaintime. This governs neuronal excitability and also the tendency of a cellto undergo repetitive firing. An ability to modify the functioning ofthese channels by chemical means is likely to produce therapeuticallyuseful agents. So far the agents which are known to block the TOCchannels are toxins such as the snake toxin dendrotoxin, or4-aminopyridine and its derivatives. Blockade of the TOC channels leadsto a change in the pattern of transmitter release and depending upon thepattern and type of neurone affected different therapeutic ends willresult. For example TOC blockers which increase dopaminergictransmission in the substantia nigra will be of use in treatment ofParkinson's disease. Likewise, an increase in cholinergic function is ofuse in Alzheimer's disease and in cognition enhancement. Because of thecomplicated neural networks in the brain blockade of the TOC may alsolead to increase in more than one transmitter substance at a time andthis can act synergistically where a disease state is associated withmore than one transmitter deficit as is often the case. It is evident,therefore that TOC blockers may be of use in areas of depression. pain,psychoses, cognition, memory and learning, anxiety, Parkinson's diseaseand Alzheimer's disease. In addition they can be used as a treatment forconditions where there is an impairment of nerve transmission such asmultiple sclerosis.

Compounds which act to increase channel funciion may be termed channelopeners and these serve to increase the braking action of the channelson the cells. In this respect they will also reduce the likelihood ofthe cells to undergo repetitive firing and may be used asanticonvulsants in the treatment of epilepsy. Also, their action toreduce neurotransmitter release means that they may be used asanaesthetics, analgesics, sedatives and anxiolytics.

This invention provides compounds of generic formula (I): ##STR3## or apharmaceutically acceptable salt thereof, where the dotted linerepresents an optional bond,

one of R¹ and R⁵ represents hydrogen, C₁ -C₆ alkyl, C₇ -C₁₆ alkyl,--(CHR⁶)_(n) CHR⁷ CN, --(CHR⁶)_(n) CHR⁷ CONH₂, --(CHR⁶)_(n) CHR⁷ COOR⁸,--(CHR⁶)_(n) CHR⁷ CH₂ OH wherein n is 0 or 1, R⁶ and R⁷ independentlyrepresent hydrogen, C₁ -C₆ alkyl- or C₇ -C₁₆ alkyl-, and R⁷ alsorepresents hydroxy(C₁ -C₆)alkyl-, (C₂ -C₇)alkanoyloxy(C₁ -C₆)alkyl-, (C₁-C₆ alkoxy)carbonyl- and R⁸ is hydrogen or C₁ -C₆ akyl;

the other of R¹ and R⁵ is hydrogen, C₁ -C₆ alkyl or C₇ -C₁₆ akyl;

R³ is an optionally substituted C₆ -C₁₀ aryl or heteroaryl group; saidheteroaryl group containing 5 to 10 ring atoms of which one or more (e.gup to 3) of said atoms are heteroatoms selected from oxygen, nitrogenand sulphur, the same or different; said aryl or heteroaryl radicalsbeing optionally substituted by one or more substituents the same ordifferent, eg substituents commonly used in pharmaceutical chemistrysuch as for example: C₁ -C₆ alkyl; C₁ -C₆ alkoxy or such groupssubstituted by C₆ -C₁₀ aryl or heteroaryl as defined above; halogen;haloC₁ -C₆ alkyl; haloC₁ -C₆ alkoxy; carboxy; hydroxy(C₁ -C₆)alkyl; (C₁-C₆ alkoxy) carbonyl; amino including substituted amino, e.g mono- ordi- (C₁ -C₆ alkyl)-amino; nitro; hydroxy; mercapto; C₁ -C₆ alkylthio;(C₁ -C₆)alkyl carbonyl; (C₆ -C₁₀ aryl)carbonyl; (C₂ -C₇)alkanoyloxy: (C₇-C₁₁)aroyloxy; (C₁ -C₆)alkylcarbonylamino, (C₆ -C₁₀ aryl)carbonylamino;(C₂ -C₇) alkoxycarbonylamino; C₆ -C₁₀ aryl; heteroaryl as defined above;or C₁ -C₂ alkylenedioxy;

R² and R⁴ independently represent hydrogen, or a group of formula--CR^(a) R^(b) R^(c) where R^(a), R^(b) and R^(c) are independentlyselected from hydrogen, C₁ -C₆ alkyl, optionally substituted C₆ -C₁₀aryl, optionally substituted heteroaryl, C₁ -C₆ alkyl substituted byoptionally substituted C₆ -C₁₀ aryl or heteroaryl in which thesubstituent(s) is/are for example as illustrated above in connectionwith R³ ; or R² also represents COR¹¹ where R¹¹ is C₁ -C₆ alkyl, C₁ -C₆alkoxy or an optionally substituted (C₆ -C₁₀ aryl)alkyl or a heteroarylalkyl radical: said heteroaryl group containing 5 to 10 ring atoms ofwhich one or more (e.g up to 3) of said atoms are heteroatoms selectedfrom oxygen, nitrogen and sulphur, the same or different; said aryl orheteroaryl radicals being optionally substituted by one or moresubstituents the same or different, eg substituents commonly used inpharmaceutical chemistry such as for example: C₁ -C₆ alkyl, C₁ -C₆alkoxy, or such groups substituted by C₆ -C₁₀ aryl or heteroaryl asdefined above: halogen; halo C₁ -C₆ alkyl, halo C₁ -C₆ alkoxy; carboxy;hydroxy(C₁ -C₆)alkyl C₂ -C₇ alkanoyloxy(C₁ -C₆)alkyl; (C₁ -C₆alkoxy)carbonyl; amino including substituted amino, e.g mono- or di- (C₁-C₆ alkyl)-amino; nitro; hydroxy; mercapto; C₁ -C₆ alkyhhio; (C₁ -C₆alkyl)carbonyl; (C₆ -C₁₀ aryl)carbonyl: (C₂ -C₇)alkanoyloxy; (C₇-C₁₁)aroyloxy; (C_(l) -C₆ alkyl)carbonylamino, (C₆ -C₁₀aryl)carbonylamino; (C₂ -C₇ alkoxycarbonyl)amino; C₆ -C₁₀ aryl;heteroaryl as defined above; or C₁ -C₂ alkylenedioxy;

one of Y and Y₁ is ##STR4## where R¹³ represents hydrogen, C₁ -C₆ alkylor C₇ -C₁₆ aralkyl;

the other of Y and Y₁ is --CHR¹² -- where R¹² is hydrogen, C₁ -C₆ alkylor C₇ -C₁₆ aralkyl.

As used herein, examples of alkyl as a group or part of a group, e.garalkyl, alkanoyl, are straight or branched chain groups of up to 6carbon atoms especially of 1 to 4 carbon atoms such as methyl, ethyl,n-propyl, isopropyl, n-butyl and sec butyl. Examples of "alkoxy" as agroup or part of a group, e.g alkoxycarbonyl, are groups of formulaalkyl-O- where alkyl has the meanings immediately above. Examples ofaryl as a group or part of a group, e.g aralkyl, aralkanoyl, are mono-or bicyclic groups of 6 to 10 carbon atoms such as phenyl and naphthyl,e.g 1 or 2-naphthyl. Heteroaryl groups have heteroatoms selected fromoxygen, nitrogen and/or sulphur. Examples of heteroaryl as a group orpart of a group, e.g heteroarylalkyl, are mono- or bicyclic groups of 5to 10 ring atoms such as those having one nitrogen heteroatom e.g 2 or3-pyrrolyl, 2, 3 or 4-pyridyl, quinolyl (e.g 2, 3 or 6-quinolyl)isoquinolyl (e.g 1-, 3- or 6-isoquinolyl); one sulphur atom, e.g 2- or3-thienyl or benzothienyl (e.g 2, 3 or 6-benzothienyl); or one oxygenatom, e.g 2- or 3-furanyl or benzofuranyl (e.g 2-, 3- or6-benzofuranyl); or two or more heteroatoms e.g thiazolyl (e.g2-thiazolyl), imidazolyl (e.g 2-imidazolyl); oxazolyl (e.g 2-oxazolyl).

R³ may be for example phenyl or phenyl substituted by one or moresubstitutents as illustrated above, e.g substituents the same ordifferent selected from: C₁ -C₆ alkoxy such as methoxy, ethoxy; halogensuch as chlorine or bromine; CF₃ ; CF₃ O; C₁ -C₆ alkyl such as methyl orethyl; hydroxy; cyano and carboxy. Preferred values for R³ aremethoxyphenyl, e.g 4-methoxyphenyl and hydroxyphenyl, e.g4-hydroxyphenyl.

Examples of the group Y (and Y₁ ) are CH₂, CO and CHOH.

The values of R⁴ and R² are for example hydrogen or a group of formula--CR^(a) R^(b) R^(c) where R^(a) and R^(b) are independently selectedfrom hydrogen, methyl ethyl, propyl, isopropyl or butyl and R^(c) isselected from hydrogen, methyl, ethyl, isopropyl, propyl, butyl or a C₆-C₁₀ aryl or a heteroaryl group containing 5-10 ring atoms of which oneor more of said atoms are heteroatoms selected from oxygen, nitrogen andsulphur in which said aryl and heteroaryl moieties are optionallysubstituted as illustrated above.

Preferably R² is hydrogen and R⁴ is --CR^(a) R^(b) R^(c) where R^(a) ishydrogen, R^(b) is methyl and R^(c) is optionally substituted aryl suchas phenyl or substituted phenyl such as illustrated above. R² may alsobe COCH₃, COOCH₃ or COCH₂ Ph.

Preferred compounds of formula I have R³ represents 4-methoxyphenyl.Also preferred are compounds where R² represents methyl or hydrogen.

Examples of R¹ and R⁵ are hydrogen, Me, Et, ^(n) Pr, benzyl, --(CH₂)₂OH, --CH₂ CH₂ CN, --(CH₂)₂ COOMe, and --(CH₂)₂ COOEt.

Particularly preferred are compounds of formula IA: ##STR5## in whichformula R¹ is hydrogen, C₁ -C₆ alkyl, or CH₂ CH₂ COOR⁸ ; R³ is asdefined above, preferably unsubstituted or substituted phenyl. e.g wherethe substituents is/are selected from C₁ -C₆ alkyl, C₁ -C₆ alkoxy,hydroxy, halogen and methylene or ethylene-dioxy; R^(4') is hydrogen,alkyl or optionally substituted aryl(C₁ -C₆) alkyl in which the alkylgroup is itself optionally substituted by C₁ -C₆ alkyl, and R⁸ ishydrogen or C₁ -C₆ alkyl.

Examples of R^(4') include phenylmethyl or α-methylphenylmethyl in whichthe phenyl group is optionally substituted by substituents as listedabove.

Preferred values for R^(4') are PhCH(Me)--, PhCH₂ -- and H.

The compounds of formula I can possess one or more asymmetric centresand accordingly the compounds may exist and be isolated in a number ofoptically active stereoisomeric foes. Geometric isomers (,e.g. E and Z;cis and trans) are also obtained when R³ is bonded via a double bond.This invention encompasses the compounds of formula I in any opticallyactive or geometric form or mixtures thereof eg, racemates ordiastereoisomers. Standard separation techniques may be used to isolateparticular enantiomeric and diastereomeric forms. For example a racetalcmixture may be converted to a mixture of optically activediastereoisomers by reaction with a single enantiomer of a `resolvingagent` (for example by diastereomeric salt formation or formation of acovalent bond). The resulting mixture of optically activediastereoisomers may be separated by standard techniques (e.gcrystallisation or chromatography) and individual optically activediastereoisomers then treated to remove the `resolving agent` therebyreleasing the single enantiomer of the compound of the invention. Chiralchromatography (using a chiral support, eluent or ion pairing agent) mayalso be used to separate enantiomeric mixtures directly.

Stereospecific synthesis using optically active starting materialsand/or chiral reagent catalyst and/or solvents may also be employed toprepare particular diastereoisomers or even a particular enantiomer.

The compounds of formula I possess pharmacological activity inparticular they block voltage gated potassium chanels. They maytherefore be used to treat CNS disorders as described above such asdepression, pain psychoses, anxiety, movement disorders (such asParkinson's disease) and multiple sclerosis and in enhancing cognition,memory and learning. They demonstrate their ability to block voltagegated potassium channels in dorsal root ganglion cells by the followingstandard test procedures:

PROCEDURE 1

Modulation of voltage-activated K+ currents in dorsal root ganglion(DRG) cells:

The method used in the culture or dorsal root ganglion cells is similarto that described by Wood el. at., Capsaicin induced ion fluxes indorsal root ganglion cells in culture, J. Neuroscience, 8, 3208-3220)(1988L Dorsal root ganglia are dissected mainly from around the lumbarand thoracic vertebrae and placed in a conical centrifuge tubecontaining Ham's F14 nutrient mixture (F14:Imperial Laboratories) plushorse serum (HS: GIBCO or Flow). When all ganglia have been collected(ex ca. 14 pups) the excess medium is removed and the ganglia incubatedfor 30 min in "F14+HS" containing 0.1% collagenase Type 1A-S (Sigma).Excess medium is removed, ganglia washed in 4 ml F14 (no HS),resuspended and spun down at 900 g for 10 s. The supernatant is againremoved and replaced with 1.8 ml F14 (no HS) plus 0.2 ml trypsin (GIBCO)at a final concentration of 0.25%. The ganglia are then incubated at 37°C. for 30 min agitating every 10 min to prevent clumping. Thetrypsinisation is inhibited by the addition of 6 ml "F14+HS" and cellsare resuspended and centrifuged as before. The medium is removed and 2ml added of "F14 +HS" containing 0.4% DNAase 1 (Sigma). The ganglia arethen triturated gently 15-20× using a siliconised pasteur pipette,filtered through a 90 mm nylon mesh filter and collected into acentrifuge tube. The filter is further washed with 2 ml of "F14 +HS"which is collected into the same tube. The suspension is spun at 900 gfor 3 min, the supernalant removed and the cells resuspended in DRGGrowth Medium (DRG-GM) which consists of: HAMS F14 nutrient mixture(40%, v/v), HS(10%, v/v) C6 conditioned medium (50%, v/v),penicillin/streptomycin (100U/ml; 100 μg/ml) and NGF (30 μg/ml). Cellsare then plated out onto five 60mm poly-L-lysine-coated tissue culturepetri dishes (see below).

Replating

After a few days in culture (3-7 days, usually), cells are resuspendedfrom 60 mm dishes using a 0.25% solution of trypsin in F14. An equalvolume of DRG-GM is added to inhibit the trypsin, the cells are spun at900 g for 5 minutes and resuspended in 0.25-0.5 ml of DRG-GM. Neuritesare removed by gentle trituration through a 21 g syringe needle (15-20strokes) and a drop of the cell suspension is then placed on each of 5-6poly-D-lysine- and laminin-coated 35 mm petri dishes (see below). After30 minutes incubation at 37° C., each plate is flooded with ca 1.5 mlDRG-GM and after about 1 hour incubation, cells are ready forelectrophysiological recording. This final step is carried outspecifically in order to remove neurites which hinder good voltage-clampof the cells.

Coating of plates

2ml of poly-D-lysine (Sigma), reconsitituted in distilled water to 100μg/ml, are added to each plate and left for 1-2 hours. Plates are thenwashed with water and left to dry. Laminin (5 μg/ml) is added as a dropto the centre of plates (previously coated with poly-D-Lys), left for 45min before removal of excess and use of plates.

Electrophysiology

Recordings are made using an AxoClamp-2A (Axon Instruments Inc)switiching damp amplifier using patch electrodes (4-8M ohms), made fromborosilicate glass capillary tubes (GC150TF-10, Clark Electromedical)and fire-polished. Electrodes are filled with (in mM): 140K Gluconate, 2MgCl₂, 1.1 EGTA/KOH, 5 HEPES, 20 sucrose, 2 MgATP, 0.2 GTP; pH set to7.2 with KOH and osmolarity adjusted with sucrose to 310 mOsm. Theelectrodes are then and dipped in Sigmacote (Sigma) prior to recordingto reduce stray capacitance. The bathing solution in which cells arecontinually perfused (during recordings) consists of (in mM): 124 NaCl,2.5 KCl 4 MgCl₂. 5 HEPES, 10 glucose, 1 μM TTX, 20 sucrose pH set to 7.4with NaOH and osmolarity adjusted with sucrose to 320 mOsm. Ca²⁺ isomitted from the bathing medium in order to miniraise voltage-activatedCa²⁺ currents and Ca²⁺ activated K+ currents. TTX is included to blockvoltage-activated Na⁺ currents, although in some recordings a residualTTX-resistant Na⁺ current is evident. Recordings are made involtage-clamp mode using a voltage-step protocol consisting of:

i) holding potential (V_(h))=-30 mV (in order to inactivate transientoutward current)

ii) 1 s prepulse to -100 mV

iii) 1 s pulse to +60 mV to activate total outward current

iv) return to -30 mV

In some cases current-voltage (I-V) relationships are obtained in thepresence and absence of test compound by constructing families ofvoltage steps over a range of membrane potentials (-100 mV to +60 mV)from a holding potential of either -30 mV or -100 mV. Voltage steps anddata acquisition (current responses) are controlled by an Atari MegaSTEcomputer interfaced to the voltage-clamp via an ITC-16 ADC/DAC(Instrutech Corp.) and subsequent analysis carried out using REVIEW(Instrutech Corp). Test compounds are applied to individual neurones bya local microperfusion system, initially at a test concentration of 10μM (solubility-permitting).

CALCULATIONS

Current responses during the test voltage step to +60 mV (above) aremeasured off-line using REVIEW (Instrutech Corp). The followingmeasurements are made:

peak (with ca.50 ms) and Q integral (t═1 s) outward current measured at+60 mV:

i) after conditioning prepulse to -100 mV (includes noninactivating aswell as transient outward current (TOC)

ii) without conditioning prepulse (mainly non-inactivating current)

iii) difference (digital subtraction) of above currents corresponds toTOC).

Current amplitudes are obtained for: total outward current (K₋₁₀₀)noninactivating current (K₋₃₀) and TOC. Peak current amplitudes recordedin the presence of test compounds are expressed as a percentage of thecorresponding control values.

Standard Compounds

4-aminopyridine ( 100% block of TOC at 1 mM) Toxin I (50% block of TOCat 100 mM) (Toxin I is a dendrotoxin homologue.)

PROCEDURE 2

Compounds of this invention were tested for blocking activity on theMK-1 voltage-activated K+ channel; according to the following standardtest procedure:

CHO cells stably transfected with cDNA for MK-1 (Dr B Tempel et. alUniversity of Washington, Nature, 332, 837-839 (1988)) were maintainedin tissue culture using standard procedures and media for this cellline. Cells were plated on 35 mm plastic dishes and used subsequentlyfor electrophysiology within 3 days.

Currents were recorded using the whole-cell voltage-clamp configurationof the patch clamp technique, using an Axopatch IC amplifier (AxonInstruments). Patch electrodes were manufactured from aluminosilicateglass tubing and heat polished prior to use. No electrode coating wasnecessary for whole-cell recording. Signal acquisition and analysis wasperformed using pClamp software (Axon Instruments). A p/4 subtractionprocedure was used to remove leak and capacitive currents on line. Aholding potential of -100mV was routinely used.

Two main protocols were used in testing drugs. 1) Current-voltage (I-V)curves were collected, with incrementing steps of either 10 or 20 mV.Full I-V curves were obtained both in control and drug solutions. 2) A`pharmacology` programme, which involved single voltage steps from -100mV to +60 mV, applied and collected at 20 s intervals. Compounds underinvestigation were applied via a `U` tube rapid perfusion system to asmall area of the recording chamber. Drug applications were alwaysbracketed by control solutions to ensure reversibility. The recordingchamber was continuously perfused at 3 ml.min⁻¹. Results are expressedas % of control peak current (at +60 mV). However, where drugs have atime dependent effect on MK- 1. i.e acceleration of decay, results arealso expressed as a % of total charge transferred within the duration ofthe voltage step.

The standard extracellular solution contained (in mM): NaCl 135, KCl 5,MgCl₂ 4, EGTA 1, HEPES 10 and glucose 25, set to pH 7.4 with NaOH. Theintracellular (pipette) solution comprised: K aspartate/K gluconate 120,KCl 20, MgCl₂, MgATP 2, EGTA 10, HEPES 10, pH at 7.4 with NaOH. Thissolution was stored in 1 ml aliquots at -4° C., and filtered at 0.2mm.The MK-1 current is a slowly rising, very slowly inactivating current,which may reach several nA in amplitude at +60 mV.

    ______________________________________                                        STANDARD COMPOUNDS:                                                           Compound     Concentration                                                                             % Peak Control Current                               ______________________________________                                        4-aminopyridine                                                                            0.1     mM      36                                               4-aminopyridine                                                                            2       mM      91                                               Tetraethylammonium                                                                         10      mM      92                                               Toxin I      100     nM      90                                               Quinine      100     μM   75                                               ______________________________________                                    

RESULTS

Results for representative compounds of this invention in the twoabovementioned tests are shown in the Table below:

    ______________________________________                                        COMPOUND       % Block of TOC                                                 EXAMPLE  CONCEN-   PROCEDURE 1  PROCEDURE 2                                   NO       TRATION   DRG %        mKv 1.1 (CHO) %                               ______________________________________                                        1        10 μM  --           33                                            2        10 μM  18           --                                            3        10 μM  --           50                                            5A       10 μM  --           52                                            5B       10 μM  --           46                                            ______________________________________                                    

The results show the ability of compounds of this invention to blockvoltage gated potassium channels in cells indicating pharmaceutical usesas described hereinabove.

This invention also provides processes for preparing the compoundsformula I and IA.

Many starting materials used herein can be derived from substitutedcatechols, reduced to give or form many known cyclohexane-1,3- or -1,4-diones appropriately protected to give compounds of the type:##STR6## where R is R¹, R⁵, R¹² or R¹³ or a group convertible thereto,and R³ is as defined herein.

The group R may be introduced into the ring via alkylation procedurestreatment with lithium and a halide, such as an alkyl halide.

Compounds of formula I may be prepared by one of the following processeswhere if necessary reactive substituent groups are protected prior toreaction and removed thereafter; said processes comprising:

(A) reacting a compound of formula: ##STR7## wherein R¹, R², R⁴, R⁵ andR¹² are as defined herein, with an aldehyde of formula R³ CHO, in thepresence of base to give a corresponding compound of formula I which hasoxo group in the 3-position and the optional bond to to the 4-positionis present or

(B) reacting a compound of formula: ##STR8## wherein R¹, R², R⁴, R¹² andR¹³ and R⁵ are as defined above with an anion of formula:

    R.sup.3 CH.sub.2.sup.⊖

where R³ is as defined above, e.g using a Grignard reagent, to give acorresponding compound of formula I having a 4-hydroxy group, whichcompound may be dehydrated to give a compound of formula I wherein theoptional bond to the 4-position is present; or

(C) reacting a compound of formula (III) as defined above with a Wittigreagent of formula:

    (Ph).sub.3 P═CHR.sup.3

wherein R³ is as defined above to give a corresponding compound offormula I where the optional bond to the 4-position is present; or

(D) reacting a compound of formula (IV): ##STR9## wherein R¹, R², R⁴,R⁵, R¹² and R¹³ are as defined above, (R¹⁸)₃ is defined as three R¹⁸radicals the same or different selected from alkyl, cycloaIkyl, aralkyl,aryl or electron donating substituents such as alkoxy, cycloalkoxy,aralkoxy, aryloxy, alkylthio, cycloalkythio, aralkylthio or arylthio,the group R^(d) R^(e) N-- where R^(d) and R^(e) are selected from alkyl,cycloalkyl, aryl and aralkyl or R^(d) and R^(e) are joined to form aheterocyclic ring with the nitrogen atom to which they are attached (e.gpiperidinyl. pyrrolidinyl which may be substituted. e.g by alkyl) and X¹is sodium, potassium or lithium, with a compound of formula:

    R.sup.3 CHO

wherein R³ is as defined above in connection with formula I; followed bytreatment under acidic or basic conditions, to give a compound offormula I in which the optional bond to the 4-position is present; or

(E) reacting a compound of formula (III) as defined above with acompound of formula: ##STR10## where R³, R¹⁸ and X¹ are as definedabove, followed by treatment under acidic or basic conditions, or

(F) converting a compound of formula I having at least one reactive siteor substituent group to give a different compound of formula I; or

(G) reducing a compound of formula (VI): ##STR11## wherein R¹, R², R³,R⁴ and R⁵ are as defined above, e.g catalytically using 5% Pd/C andhydrogen: to give a saturated compound of formula I: or

(H) converting a basic compound of formula I to an acid addition orquaternary ammonium salt thereof, or vice versa, or

(I) resolving a mixture of isomeric compounds of formula I to isolate aspecific enantiomeric form substantially in the absence of otherisomers, or

(J) reacting a compound of formula: ##STR12## where R¹, R³, R⁵ R¹², andR¹³ are as defined above, with a compound of formula R⁴ NH₂ where R⁴ isas defined above, (e.g an amine or an ammonia source such as ammoniumacetate) and reducing to give a compound of formula I wherein R² ishydrogen. or

(K) hydrogenating a compound of formula I where R⁴ is a group of formula--CR^(a) R^(b) R^(c) wherein at least one of R^(a), R^(b) and R^(c) isoptionally substituted aryl to give a compound of formula I wherein R⁴is hydrogen: or

(L) alkylating a compound of formula I wherein R² is hydrogen with ahalide of formula hal--CR^(a) R^(b) R^(c) where hal is a halogen e.g.bromine to give a corresponding compound of formula I: or

(M) reacting a compound of formula ##STR13## with a Grignard reagent offormula R¹³ Mghal where R¹³ is C₁ -C₆ alkyl or C₇ -C₁₆ aralkyl and halis a halogen and reducing the product to give a corresponding compoundof formula I wherein Y is --CHR¹³.

Methods for carrying out processes (A)--(M) are known in the literatureand may be carried out by standard procedures. If required other sitesin the molecule can be protected by known methods to avoid sidereactions.

Process (A) is conveniently carried out by heating in the presence of asmall amount of organic base, e.g piperidine. When --NR² R⁴ representsNH-- or a secondary amine, it is preferably protected in the form of anacetyl derivative which can be removed after reaction using basichydrolysis.

Processes (B) and (M) may be carried out using a Grignard reagent offormula R³ CH₂ Mghal where hal is halogen, e.g. bromine.

Process (C) may be carried out under Wittig reaction conditions usingthe desired substituted triphenylphosphonium halide. Processes forcarrying out Wittig reactions are extensively described in theliterature. See for example Org. React. 14, 270 (1965) and Org. Syn.Coll. Vol. 5 751 (1973).

Process (D) may be carried out under Peterson reaction conditions. Inthe process an intermediate of formula IV in which X¹ is R³ CH(OX)-- (Xis Li, Na or K) is formed and this compound is hydrolysed to the alcoholand dehydrated by acid or base treatment, removing any protection groupsas required. Process (E) is analogous to Process (D) and may be carriedunder the same conditions.

With regard to process (F) conversions may be carried out by knownmeans, e.g an alcohol may be formed from an ester substitutent byreduction using lithium borohydride with heating if desired in thepresence of an inert solvent, e.g tetrahydrofuran. Process (F) alsoincludes conversion of substituents on R⁴ and/or R³ when each representsan aromatic radical. Such methods are well known in the art. For examplean alkoxy substiuent can be converted to hydroxy using boron tribromide.An arylmethoxy substituent can be hydrogenated to give hydroxy. Nitrosubstituents can be reduced to amino substituents. Amino substituentscan be acylated e.g using an acyl halide to give acylaminoo orsulphonylated to give a sulphonamide, or alkylated to give analkylamino, e.g by reductive alkylation when R¹ is hydrogen a Michaeladdition may be used to prepare compounds of formula I wherein R¹ --CHR⁶CHR⁷ CN, --CHR⁶ CHR⁷ COOR⁸ or --CHR⁶ CHR⁷ CONH₂.

Process (G) may be conveniently carried out using a reducing agent, e.ga trialkylsilane under acidic conditions such as trifiuoroacetic acid.As a by-product hydroxy substitution can also occur to give a compoundof formula I wherein R⁵ is hydroxy in the 4 position.

Process (J) may be carried out by reacting a compound (VII) as definedhereinabove with an amine of formula R⁴ NH₂ to give an imine andreducing the imine. Suitable methods for reducing the imine arecatalytic hydrogenation, e.g using Raney nickel and hydrogen, or using areducing agent such as an alkali metal borohydride (e.g sodiumborohydride or sodium cyanoborohydride). In the case of the latterreducing agents the reduction may be carried out simultaneously withimine formation so that the net effect is reductive animation. Raneynickel hydrogenation of 2-substituted cyclohexylimines generally gives acis-reduced product, i.e where the hydrogen in the 1 and 2 position areboth cis configuration. Borohydride reduction on the other hand gives amixture of cis and trans configuration of hydrogens in the 1 and 2positions.

Process (K) may be carried out by catalytic hydrogenation e.g usingpalladium on carbon catalyst under acidic conditions such as glacialacetic acid.

Process (L) may be carded out in an inert solvent in the presence ot atertiary amine, e.g. Et₃ N.

As mentioned above standard resolution techniques can be used in process(I) to isolate enantiomeric forms of the compounds of formula I. Suchtechniques are well known in the art.

Where necessary in the reactions described herein protecting groups maybe used to protect reactive sites during a reaction and removedthereafter.

Once a compound of formula I is prepared containing a reactivesubstituent group or site, e.g an alkanoyloxy substituent,or an acidicproton, then such compounds may be converted to a different compound offormula I e.g hydrolysed to give corresponding hydroxy compounds offormula I. Similarly compounds of formula I containing a hydroxy groupmay be acylated, e.g using alkanoyl halides to give correspondingalkanoyl compounds of formula I. Similarly when an alkoxy substituent ispresent then such compounds may be dealkylated using standard proceduresto give corresponding hydroxy compounds of formula I. Accordinglycompounds of formula I may also be intermediates for other compounds offormula I.

As discussed above starting materials for the processes described hereinare known compounds or can be made by analogous methods for knowncompounds.

For example compounds of formula (VHI) wherein R¹ is --CHR⁶ CHR⁷ CN canbe prepared by Michael addition to an enamine (formed from a cyclicketone) as shown in Reaction Scheme I below: ##STR14## where R¹ is CHR⁶CHR⁷ CN. Similarly a compound of forrnula (VIII) wherein R¹ is --CHR⁶CHR⁷ COOR⁸ can be prepared by the above reaction but using an acrylicester of formula: ##STR15## instead of an acrylonitrile. In these tworeactions Y and Y₁ represent --CHR¹³ -- and CHR¹² -- respectively.

Compounds of formula I also possess at least tw_(o) asymmetric centresand therefore isomers, enantiomers and diastereoisomers and mixturesthereof, are obtainable. Similarly E and Z isomers are obtainable when Xis R³ CH═C. All such isomers are within the scope of this invention.

Examples of compounds of formula (1) are:

methyl(1'R,1S,2R,5R)-5-((4-methoxyphenyl)methyl-2-(1'-phenylethylamino)-cyclohexanepropionate(Example 1 ); and

methyl (1'R,1S,2R,5S)-5-((4-methoxyphenyl)methyl-2-(1'-phenylethylamino)-cyclohexanepropionate(Example 2) and its monohydrochloride salt.

The compounds of this invention may be obtained in free base form or asacid addition salts as desired. Examples of such salts include saltswith pharmaceutically acceptable organic or inorganic acids such ashydrochloric, hydrobromic, hydroiodic, sulphuric, phosphoric, nitric,acetic, citric, tartaric, fumaric, succinic, malohic, formic, maleicacid or organosulphonic acids such as methane sulphonic or p-toluenesulphonic acids.

When acidic substituents are present it is also possible to form saltsby treatment with bases, to give for example alkali metals (such assodium) or ammonium salts. Such salts of the compounds of formula I areincluded within the scope of this invention.

When basic substituents are present then quaternary ammonium salts maybe formed by quaternizing with an alkylating agent such as alkyl oraralkyl halides.

This invention also provides pharmaceutical compositions comprising acompound of formula I or a pharmaceutically acceptable salt thereof anda pharmaceutically acceptable carrier.

For the pharmaceutical compositions any suitable carrier known in theart can be used. In such a composition, the carrier may be a solid,liquid or mixture of a solid and a liquid. Solid form compositionsinclude powders, tablets and capsules. A solid carrier can be one ormore substances which may also act as flavouring agents, lubricants,solubilisers, suspending agents, binders, or table disintegratingagents; it can also be encapsulating material. In powders the carrier isa finely divided solid which is in admixture with the the finely dividedactive ingredient. In tablets the active ingredient is mixed with acarrier having the necessary binding properties in suitable proportionsand compacted in the shape and size desired. The powders and tabletspreferably contain from 5 to 99, preferably 10-80% of the activeingredient. Suitable solid carriers are magnesium stearate, talc, sugar,lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose,sodium carboxymethyl cellulose, a low melting wax and cocoa butter. Theterm "composition" is intended to include the formulation of an activeingredient with encapsulating material as carrier, to give a capsule inwhich the active ingredient (with or without other carrier) issurrounded by carriers, which is thus in association with it. Similarlycachets are included. Sterile liquid form compositions include sterilesolutions. suspensions, emulsions, syrups and elixirs.The activeingredient can be dissolved or suspended in a pharmaceuticallyacceptable carrier, such a sterile water, sterile organic solvent or amixture of both.

The active ingredients can often be dissolved in a suitable organicsolvent, for instance aqueous propylene glycol containing from 10 to 75%of the glycol by weight is generally suitable. Other compositions can bemade by dispersing the finely-divided active ingredient in aqueousstarch or sodium carboxvmethyl cellulose solution, or in a suitable oil,for instance arachis oil. The composition may be administered orally,nasally, rectally or parenterally.

Preferably the pharmaceutical composition is in unit dosage form, thecomposition is sub-divided in unit doses containing appropriatequantities of the active ingredient; the unit dosage form can be apackaged composition, the package containing specific quantities ofcompositions, for example packeted powders or vials or ampoules. Theunit dosage form can be a capsule, cachet or tablet itself, or it can bethe appropriate number of any of these in packaged form. The quantity ofactive ingredient in a unit dose of composition may be varied oradjusted from 1 to 500 mg or more, e.g 25 mg to 250 mg, according to theparticular need and the activity of the active ingredient. The inventionalso includes the compounds in the absence of carrier where thecompounds are in unit dosage form. Based on the results from animalstudies the dosage range for the treatment of humans using a compound offormula I will be in the range from about 1 mg to 2 g per day dependingon the activity of the compound and the disease to be treated.

For certain of the abovementioned conditions it is clear that thecompounds may be used prophylactically as well as for the alleviation ofacute symptoms. References herein to "treatment" or the like are to beunderstood to include such prophylactic treatment, as well as treatmentof acute conditions.

Compounds of formula I wherein one of R¹ and R⁵ represents --(CHR⁶)_(n)CHR⁷ CN or --(CHR⁶)_(n) CHR⁷ COOR⁸ wherein n is 1 and R⁶, R⁷ and R⁸ areas defined above are direct intermediates to pharmaceutically activecompounds of formula: ##STR16## wherein R³, R⁴, R⁶, R⁵, R⁷, Y and Y₁ thedotted line are as defined above, by cyclising a compound of formula:##STR17## wherein Y₁, Y, R³, R⁴, R⁵, R⁶, R⁷ and COOR⁸ are as definedabove.

The following Examples illustrate the invention and methods forpreparing compounds of the invention. In the Examples relativeconfigurations of optical centres are denoted using the R,S notation.

EXAMPLE 1 Methyl(1'R,1S,2,R5S)-5-((4-methoxyphenyl)methyl)-2-(1'-phenylethylamino-cyclohexanepropionate

2-(Methoxycarbonylethyl)-4-(4-methoxybenzyl)cyclohexanone (t 18 g, 0.399mol) was dissolved in toluene (1 l) with R-(+)-α-methylbenzylamine (52g, 0.43 mol) and p-toluenesulphonic acid (0.2 g). The reaction mixturewas heated under reflux in a Dean Stark apparatus for 24 hours. Thesolvent was removed under vacuum and the residue was hydrogenated inethanol (800 ml) over Raney nickel at room temperature under 50 psihydrogen for four days. The catalyst was filtered off and the solvent ofthe liltrate was then evaporated under vacuum. The resulting oil wasthen chromatographed on a silica gel with a diisopropyl ether and hexanesolvent system (ratio 1:1). The first fraction yielded the titlecompound (50.5 g, 32% yield) which was 98% pure. A portion of the titlecompound (14.98 g), was converted to the dihydrochloride salt. This wasachieved by dissolving in a minimum amount of diethyl ether and thendiluting with hexane. Ethereal hydrochloric acid was added dropwiseuntil precipitation was completed. The solid was filtered and washedwith hexane then dried. ( 13.45 g). mp 96°-98° C., α!_(D) ²⁵ =+8° (1%MeOH).

Analysis: C₂₆ H₃₅ NO₃. HCl requires: C, 70.01, H. 8.14; N, 3.14

Found C, 69.72; H, 8.49; N, 3.0%.

EXAMPLE 2 (-)-Methyl(1'S,1R,2S,5R)-5-(4-Methoxphenyl)methyl)-2-(1'-phenylethylamino)cyclohexanepropionate

Methyl 5-(4'-methoxyphenylmethyl)-2-oxo-cyclohexanepropionate (98.5 g),with S-(-)α-methylbenzylamine in toluene (500 ml) with p-toluenesuphonicacid (0.2 g) was refiuxed and water was collected by means of a DeanStark apparatus. After 24 hours the solvent was removed under reducedpressure. The imine product was reduced in 4 batches with Raneynickel(1.2g) in ethanol (150 ml) and hydrogenated at 50 psi and 50° C.The catalyst was removed by filtration and the samples combined andpurified by chromatography on silica using diisopropyl ether as eluentto give (41.91 g) of the title compound.

A sample (20.1 g) was dissolved in ether and treated with ethereal HCl.A gum was formed and the ether decanted. The gum was triturated inn-hexane to give a white solid (19.5 g), mp 110°-112° C., α!_(D) ²⁶=-8°. (1% MeOH)

Analysis C₂₆ H₃₅ NO₃. HCl 0.5H₂ O requires C, 68.6; H, 8.2; N, 3.1%

Found C, 68.7; H, 8.4; N, 3.0%

EXAMPLE 3 Methyl(1'R,1S,2R,5R)-5-((4-methoxyphenyl)-2-(1'-phenylethylamino)-ethylamino)cyclohexanepropionate

A. 4-Methoxybenzylcyclohexanone (43.68 g, 0.2 mol) was dissolved intoluene (250 ml). To this solution pyrrolidine (25 ml, 0.3 mol) wasadded together with a catalytic amount of toluene-4-sulphonic acid. Thereaction mixture was refluxed with a Dean and Stark apparatus for 20hours. Once the predicted amount of water had been collected, thesolvent was removed under vacuum. Excess pyrrolidine was removed byadding a little toluene and evaporating under reduced pressure.

The resulting liquid was dissolved in methanol (200 ml) and to theresulting stirred solution methyl acrylate (18 ml, 0.2 mol) dissolved inmethanol (50 ml) was added dropwise. This was stirred for 20 hours atroom temperature.

The resulting liquid was neutralised with sodium bicarbonate and theproduct extracted into dichloromethane. The solution was then passedthrough a bed of Florasil. The solvent was evaporated leaving an oil.This material was purified by distillation.2-(2-Methoxycarbonylethyl)-4-(4-methoxybenzyl)cyclohexanone distilled at155° C., 0.05 mmHg.

B. The ketone prepared by step A (50g, 0.122 mol) was dissolved intoluene (500 ml) and R (+)-α-methylbenzylamine (18.8 g, 0.155 mol wasadded. The reaction mixture was heated under reflux with a Dean Starkapparatus for 24 hours. The solvent was removed under vacuum and theresidue was hydrogenareal in ethanol (400 ml) over Raney nickel (5 g).The catalyst was filtered off and the solvent evaporated under vacuum.The resulting oil was then chromatographed on silica with a diisopropylether solvent system. The first fraction collected was identified asmethyl (1'R, 1S,2R,5S)-5-((4-methoxyphenyl)methyl)-2-(1'-phenylethylamino)-cyclohexanepropionate(13.56 g). The second fraction collected was found to be startingmaterial (5.02 g). The third fraction collected (8.73g) was identifiedas the title compound but required further purification. This wasachieved using a second column run on basic alumina in diisopropylether. The sample recovered as a gum was 98% pure. This was thenconverted to the HCl salt by dissolving the gum in the minium amount ofdiethyl ether, diluting it with hexane (100 ml) and then adding etherealHCl until precipitation ceased. The title compound as themonohydrochloride was filtered, dried and kept under vacuum (18.5 g, mp105°-6° C.). α!_(D) ²⁵ =+87 (1% MeOH)

Analysis C₂₆ H₃₅ NO₃.HCl. requires: C, 70.0: H. 8.1: N, 3.1%

Found C, 69.7; H, 8.2; N, 3.0%

EXAMPLES 4A and 4B A)Cis-(S)-4-(4-Methoxyphenylmethyl)-N-(1'-phenylethyl)cyclohexylamine B)Trans-(S)-4-(4-Methoxyphenylmethyl)-N-(1'-phenylethyl)cyclohexylamine

4-Methoxybenzylcyclohexanone, (5 g, 0.023 mol) was dissolved in tolueneand refiuxed with (S)-(-)-phenylethylamine (2.9 ml, 0.023 mol) and acatalytic amount (2 mg) of p-toluene sulphonic acid. After 20 hours when0.4 ml of water was collected in a Dean-Stark apparatus, the solvent wasevaporated under vacuum.

The imine produced was dissolved in methanol (150 ml) and cooled to -15°C. Sodium borohydride was added to the stirring solution, (0.88 g. 0.023mol). After 2 hours the reaction was allowed to warm to roomtemperature. 2N HCl (5 m) was added dropwise and a white suspensionformed. The solution was stirred for a further 2 hours to break down theborane complex. Ammonia was then added to neutralize the solution. Theproduct was extracted into ether, dried and then the solvent wasevaporated. TIc showed two major spots present. These were separated onan alumina column in a 5% ethyl acetate, hexane solvent system and thenconverted to their corresponding hydrochloride salts.

Fraction 1 gave 1.5 g ofcis-(S)-4-(4-methoxyphenylmethyl)-N-(1'-phenylethyl)-cyclohexylaminemp=223°-225° C., α!_(D) ²⁵ =-44° (c=1, MeOH)

Analysis: C₂₂ H₂₉ NO. HCl requires: C, 73.4; H, 8.4; N, 3.9

Found: C, 73.5; H, 8.5; N, 3.7%

Fraction 2 gave 2.12 g oftrans-(S)-4-(4-methoxyphenylmethyl)-N-(1'-phenylethyl-methyl)cyclohexylaminemp=275°-277° C., α!_(D) ²⁵ =-47° (c=1, MeOH)

Analysis: C₂₂ H₂₉ NO. HCl requires: C. 73.4; H, 8.4; N. 3.9

Found: C, 73.5; H. 8.6; N. 3.9%

EXAMPLES 5A and 5B A)Trans-(R)-4-(4-Methoxyphenylmethyl)-N-(1'Phenylethylmethyl)-cyclohexylaminB)Cis-(R)-4-(4-Methoxyphenylmethyl)-N-(1'Phenylethylmethyl)-cyclohexylamine

4-Methoxybenzylcyclohexanone (5g, 0.023 mol) was dissolved in toluene(150 ml) and a catalytic amount (2 mg) of p-toluene sulphonic acid.After 20 hours the solvent was evaporated under vacuum. The imineproduced was dissolved in methanol (50 ml) and cooled to -15° C. Sodiumborohydride (0.88 g, 0.023 mol) was added to the stirred solution andafter 2 hours the reaction was allowed to warm to room temperature. 1NHCl (5 ml) was added dropwise and a suspension formed. The solution wasstirred for a further 2 hours and ammonia was then added to neutralizethe solution. The product was extracted into diethyl ether, dried andthen the solvent was evaporated. TIc showed two major spots present.These were separated on a basic alumina column in a 5% ethylacetate/hexane solvent system and converted to their correspondinghydrochloride salts by dissolving in diethyl ether, diluting with hexaneand adding ethereal HCl.

Fraction 1: 1.1g oftrans-(R)-4-(4-methoxyphenylmethyl)-N-(1'phenylethylmethyl-cyclohexylamine,hydrochloride, quarterhydrate salt, mp 275°-277° C., α!_(D) ²⁷ =40° (1%in MeOH)

Analysis: C₂₂ H₂₉ NO. HCl. 0.25H₂ O requires: C, 72.5; H, 8.4; N, 3.8

Found: C, 72.8; H, 8.4; N, 3.8%.

Fraction 2: 1.4 g ofcis-(R)-4-(4-methoxyphenylmethyl)-N-(1'-phenylethylmethyl)cyclohexylamine,hydrochloride salt, mp 223°-225° C., α!_(D) ²⁷ =34° (1% in MeOH)

Analysis: C₂₂ H₂₉ NO. HCl requires: C, 73.4; H, 8.4; N, 3.9

Found: C, 7.32; H, 8.2; N, 3.8%.

EXAMPLE 6 Methyl(1'S,1R,2S,5S)-5-(4-Methoxyphenyl)methyl)-2-(1-'Phenylethylamino)-Cyclohexanepropionate

2-(2-Methoxycarbonylethyl)-4-(4-methoxybenzyl)cyclohexanone (15 g, 0.049mol) was dissolved in toluene (100 ml) with S(-)-α-methylbenzylamine(5.97 g, 0.49 mol). The reaction mixture was heated under reflux with aDean Stark apparatus for 24 hours. The solvent was removed under vacuumand the resulting oil was hydrogenareal in ethanol (100 ml) and Raneynickel (5 g) at room temperature under 50 psi, for 4 days. The catalystwas filtered off and the solvent was then evaporated under vacuum. Theresulting oil was then chromatographed on silica gel with diisopropylether as the solvent. The first fraction was found to be(-)-methyl-(1'S,1R,2S,5R)-5-(4-methoxyphenyl)methyt)-2-(1'-phenytethytamino)-cyclohexanepropionate.The second fraction was found to be the title compound, 7.74 g. Thesample was purified on a column of basic alumina run in 10% hexane/ethylacetate. The major fraction was collected and converted to the HCl saltof the title compound (7.95 g), mp=102°-3° C., α!_(D) ²⁷ =-92° (1%methanol).

Analysis: C₂₆ H₃₅ NO₃.HCl. 0.5H₂ O requires: C, 68.6; H, 8.2: N, 3.1%

Found: C, 68.9: H, 8.2; N, 3.1%

We claim:
 1. A compound of generic formula: ##STR18## or apharmaceutically acceptable salt thereof, where the dotted linerepresents an optional bond,one of R¹ and R⁵ represents hydrogen, C₁ -C₆alkyl, C₇ -C₁₆ aralkyl, --(CHR⁶)_(n) CHR⁷ CN, --(CHR⁶)_(n) CHR⁷ CONH₂,--(CHR⁶)_(n) CHR⁷ COOR⁸, --(CHR⁶)_(n) CHR⁷ CH₂ OH wherein n is 0 or 1,R⁶ and R⁷ independently represent hydrogen, C₁ -C₆ alkyl- or C₇ -C₁₆aralkyl-, and R⁷ also represents hydroxy(C₁ -C₆)alkyl-, (C₂-C₇)alkanoyloxy(C₁ -C₆)alkyl-, (C₁ -C₆ alkoxy)carbonyl- and R⁸ ishydrogen or C₁ -C₆ alkyl; the other of R¹ and R⁵ is hydrogen, C₁ -C₆alkyl or C₇ -C₁₆ aralkyl; R³ is an optionally substituted C₆ -C₁₀ arylor heteroaryl group; said heteroaryl group containing 5 to 10 ring atomsof which one or more (e.g up to 3) of said atoms are heteroatomsselected from oxygen, nitrogen and sulphur, the same or different; saidaryl or heteroaryl radicals being optionally substituted by one or moresubstituents the same or different, eg substituents commonly used inpharmaceutical chemistry such as for example: C₁ -C₆ alkyl; C₁ -C₆alkoxy or such groups substituted by C₆ -C₁₀ aryl or heteroaryl asdefined above; halogen; halo C₁ -C₆ alkyl; halo C₁ -C₆ alkoxy; carboxy;hydroxy(C₁ -C₆)alkyl; (C₁ -C₆ alkoxy)carbonyl; amino includingsubstituted amino, e.g mono- or di- (C₁ -C₆ alkyl)-amino; nitro;hydroxy; mercapto; C₁ -C₆ alkylthio; (C₁ -C₆)alkyl carbonyl; (C₆ -C₁₀aryl)carbonyl; (C₂ -C₇)alkanoyloxy; (C₇ -C₁₁)aroyloxy; (C₁-C₆)alkylcarbonylamino, (C₆ -C₁₀ aryl)carbonylamino; (C₂ -C₇)alkoxycarbonylamino; C₆ -C₁₀ aryl; heteroaryl as defined above; or C₁-C₂ alkylenedioxy; R² and R⁴ independently represent hydrogen, or agroup of formula --CR^(a) R^(b) R^(c) where R^(a), R^(b) and R^(c) areindependently selected from hydrogen, C₁ -C₆ alkyl, optionallysubstituted C₆ -C₁₀ aryl, optionally substituted heteroaryl, C₁ -C₆alkyl substituted by optionally substituted C₆ -C₁₀ aryl or heteroarylin which the substituent(s) is/are for example as illustrated above inconnection with R³ ; or R² also represents COR¹¹ where R¹¹ is C₁ -C₆alkyl, C₁ -C₆ alkoxy or an optionally substituted (C₆ -C₁₀ aryl)alkyl ora heteroaryl alkyl radical; said heteroaryl group containing 5 to 10ring atoms of which one or more (e.g up to 3) of said atoms areheteroatoms selected from oxygen, nitrogen and sulphur, the same ordifferent; said aryl or heteroaryl radicals being optionally substitutedby one or more substituents the same or different, eg substituentscommonly used in pharmaceutical chemistry such as for example: C₁ -C₆alkyl, C₁ -C₆ alkoxy, or such groups substituted by C₆ -C₁₀ aryl orhetemaryl as defined above; halogen; halo C₁ -C₆ alkyl, halo C₁ -C₆alkoxy; carboxy; hydroxy(C₁ -C₆)alkyl C₂ -C₇ alkanoyloxy(C₁ -C₆)alkyl;(C₁ -C₆ alkoxy)carbonyl; amino including substituted amino, e.g mono- ordi-(C₁ -C₆ alkyl)-amino; nitro; hydroxy; mercapto; C₁ -C₆ alkylthio; (C₁-C₆ alkyl)carbonyl; (C₆ -C₁₀ aryl)carbonyl; (C₂ -C₇)alkanoyloxy; (C₇-C₁₁)aroyloxy; (C₁ -C₆ alkyl)carbonylamino, (C₆ -C₁₀ aryl)carbonylamino;(C₂ -C₇ alkoxycarbonyl)amino; C₆ -C₁₀ aryl; heteroaryl as defined above;or C₁ -C₂ alkylenedioxy; one of Y and Y₁ is ##STR19## where R¹³represents hydrogen, C₁ -C₆ alkyl or C₇ -C₁₆ aralkyl; the other of Y andY₁ is --CHR¹² -- where R¹² is hydrogen, C₁ -C₆ alkyl or C₇ -C₁₆ aralkyl.2. A compound as claimed in claim 1 wherein R⁴ and R² are independentlyhydrogen or a group of formula --CR^(a) R^(b) R^(c) where R^(a) andR^(b) are independently selected from hydrogen, methyl, ethyl, propyl,isopropyl or butyl and R^(c) is selected from hydrogen, methyl, ethyl,isopropyl, propyl, butyl or a C₆ -C₁₀ aryl or a heteroaryl groupcontaining 5-10 ring atoms of which one or more of said atoms areheteroatoms selected from oxygen, nitrogen and sulphur in which saidaryl and heteroaryl moieties are optionally substituted as defined inclaim
 1. 3. A compound as claimed in claim 1 wherein R³ may be forexample phenyl or phenyl substituted by one or more substitutents asillustrated above the same or different selected from: C₁ -C₆ alkoxy,halogen, CF₃, CF₃ O, C₁ -C₆ alkyl, hydroxy, cyano and carboxy.
 4. Acompound as claimed in claim 1 wherein Y₁ is CH₂.
 5. A compound asclaimed in claim 1 wherein Y is CH₂.
 6. A compound as claimed in claim 1wherein R³ is an optionally substituted phenyl or pyridyl group, saidsubstituents being selected from: C₁ -C₆ alkyl; C₁ -C₆ alkoxy or suchgroups substituted by C₆ -C₁₀ aryl or heteroaryl as defined above;halogen; haloC₁ -C₆ alkyl; haloC₁ -C₆ alkoxy; carboxy; hydroxy(C₁-C₆)alkyl; (C₁ -C₆ alkoxy)carbonyl; amino, mono- or di- (C₁ -C₆alkyl)-amino; nitro; hydroxy; mercapto; C₁ -C₆ alkylthio; (C₁ -C₆)alkylcarbonyl; (C₆ -C₁₀ aryl)carbonyl; (C₂ -C₇)alkanoyloxy; (C₇-C₁₁)aroyloxy; (C₁ -C₆)alkylcarbonylamino, (C₆ -C₁₀ aryl)-carbonylamino;(C₂ -C₇) alkoxycarbonylamino; C₆ -C₁₀ aryl; heteroaryl as defined above;or C₁ -C₂ alkylenedioxy.
 7. A compound as claimed in claim 1 wherein R¹,R⁵ and R⁶ are hydrogen.
 8. A compound of claim 1 which is methyl5-((4-methoxyphenyl)methyl-2-(1'-phenylethylamino)-cyclohexanepropionateor a pharmaceutically acceptable salt thereof.
 9. A compound of claim 1which is methyl5-((4-methoxyphenyl)-2-(1'-phenylethylamino)ethylamino)cyclohexanepropionateor a pharmaceutically acceptable salt thereof.
 10. A compound of claim 1which is methyl4-(4-methoxyphenylmethyl)-N-(1'-phenylethyl)cyclohexylamine or apharmaceutically acceptable salt thereof.
 11. A compound of claim 1which is methyl4-(4-methoxyphenylmethyl)-N-(1'phenylethylmethyl)cyclohexylamine or apharmaceutically acceptable salt thereof.
 12. A compound of claim 1which ismethyl(1'R,1S,2R,5R)-5-((4-methoxyphenyl)methyl-2-(1'-phenylethylamino)-cyclohexanepropionate;methyl(1'R,1S,2R,5S)-5-((4-methoxyphenyl)methyl-2-(1'-phenylethylamino)-cyclohexanepropionate;(-)-methyl(1'S,1R,2S,5R)-5-(4-methoxyphenyl)methyl)-2-(1'phenylethylamino)-cyclohexanepropionate;methyl(1'R,1S,2R,5R)-5-((4-methoxyphenyl)-2-(1'-phenylethylamino)ethyl-amino)cyclohexanepropionate;cis-(S)-4-(4-methoxyphenylmethyl)-N-(1'-phenylethyl)cyclohexylamine;trans-(S)-4-(4-methoxyphenylmethyl)-N-(1'-phenylethyl)cyclohexylamine;trans-(R)-4-(4-methoxyphenylmethyl)-N-(1'phenylethylmethyl)cyclohexylamine;cis-(R)-4-(4-methoxyphenylmethyl)-N-(1'phenylethylmethyl)cyclohexylamine;ormethyl(1'S,1R,2S.5S)-5-(4-methoxyphenyl)methyl)-2-(1-'phenylethylamino)-cyclohexanepropionateora pharmaceutically acceptable salt thereof.
 13. A compound of formulaIA: ##STR20## in which formula R¹ is hydrogen, C₁ -C₆ alkyl,--(CHR⁶)_(n) CHR⁷ CN, --(CHR⁶)_(n) CHR⁷ CONH₂, --(CHR⁶)_(n) CHR⁷ COOR⁸or --(CHR⁶)_(n) CHR⁷ CH₂ OH; R³ is unsubstituted or substituted phenylwhere the substituents is/are selected from C₁ -C₆ alkyl, C₁ -C₆ alkoxy,hydroxy, halogen and methylene or ethylenedioxy; and R^(4') is hydrogen,alkyl or optionally substituted aryl(C₁ -C₆)alkyl in which the alkylgroup is itself optionally substituted by C₁ -C₆ alkyl; R⁶ and R⁷independently represent hydrogen C₁ -C₆ alkyl- or C₇ -C₁₆ aralkyl-, andR⁷ also represents hydroxy(C₁ -C₆)alkyl-, (C₂ -C₇ alkanoyloxy(C₁-C₆)alkyl-, (C₁ -C₆ alkoxy)carbonyl- and R⁸ is hydrogen or C₁ -C6 alkyl;with the proviso that when R³ is unsubstituted phenyl, then R¹ andR^(4') cannot both be hydrogen.
 14. A compound as claimed in claim 13wherein R¹ is are hydrogen, Me, Et, ^(n) Pr, benzyl, --(CH₂)₂ OH, --CH₂CH₂ CN, --(CH₂)₂ COOMe, and --(CH₂)₂ COOEt.
 15. A pharmaceuticalcomposition comprising a compound of formula ##STR21## or apharmaceutically acceptable salt thereof, where the dotted linerepresents an optional bond,one of R¹ and R⁵ represents hydrogen, C₁ -C₆alkyl, C₇ -C₁₆ aralkyl, --(CHR⁶)_(n) CHR⁷ CN, --(CHR⁶)_(n) CHR⁷ CONH₂,--(CHR⁶)_(n) CHR⁷ COOR⁸, --(CHR⁶)_(n) CHR⁷ CH₂ OH wherein n is 0 or 1,R⁶ and R⁷ independently represent hydrogen, C₁ -C₆ alkyl- or C₇ -C₁₆aralkyl-, and R⁷ also represents hydroxy(C₁ -C₆)alkyl-, (C₂-C₇)alkanoyloxy(C₁ -C₆)alkyl-, (C₁ -C₆ alkoxy)carbonyl- and R⁸ ishydrogen or C₁ -C₆ alkyl; the other of R¹ and R⁵ is hydrogen, C₁ -C₆alkyl or C₇ -C₁₆ aralkyl; R³ is an optionally substituted C₆ -C₁₀ arylor heteroaryl group; said heteroaryl group containing 5 to 10 ring atomsof which one or more (e.g up to 3) of said atoms are heteroatomsselected from oxygen, nitrogen and sulphur, the same or different; saidaryl or heteroaryl radicals being optionally substituted by one or moresubstituents the same or different, eg substituents commonly used inpharmaceutical chemistry such as for example: C₁ -C₆ alkyl; C₁ -C₆alkoxy or such groups substituted by C₆ -C₁₀ aryl or heteroaryl asdefined above; halogen; halo C₁ -C₆ alkyl; halo C₁ -C₆ alkoxy; carboxy;hydroxy(C₁ -C₆)alkyl; (C₁ -C₆ alkoxy)carbonyl; amino includingsubstituted amino, e.g mono- or di- (C₁ -C₆ alkyl)-amino; nitro;hydroxy; mercapto; C₁ -C₆ alkylthio; (C₁ -C₆)alkyl carbonyl; (C₆ -C₁₀aryl)carbonyl; (C₂ -C₇)alkanoyloxy; (C₇ -C₁₁ )aroyloxy; (C₁-C6)alkylcarbonylamino, (C₆ -C₁₀ aryl)carbonylamino; (C₂ -C₇)alkoxycarbonylamino; C₆ -C₁₀ aryl; heteroaryl as defined above; or C₁-C₂ alkylenedioxy; R² and R⁴ independently represent hydrogen, or agroup of formula --CR^(a) R^(b) R^(c) where R^(a), R^(b) and R^(c) areindependently selected from hydrogen, C₁ -C₆ alkyl, optionallysubstituted C₆ -C₁₀ aryl, optionally substituted heteroaryl, C₁ -C₆alkyl substituted by optionally substituted C₆ -C₁₀ aryl or heteroarylin which the substituent(s) is/are for example as illustrated above inconnection with R³ ; or R² also represents COR¹¹ where R¹¹ is C₁ -C₆alkyl, C₁ -C₆ alkoxy or an optionally substituted (C₆ -C₁₀ aryl)alkyl ora heteroaryl alkyl radical; said heteroaryl group containing 5 to 10ring atoms of which one or more (e.g up to 3) of said atoms areheteroatoms selected from oxygen, nitrogen and sulphur, the same ordifferent; said aryl or heteroaryl radicals being optionally substitutedby one or more substituents the same or different, eg substituentscommonly used in pharmaceutical chemistry such as for example: C₁ -C₆alkyl, C₁ -C₆ alkoxy, or such groups substituted by C₆ -C₁₀ aryl orheteroaryl as defined above; halogen; halo C₁ -C₆ alkyl, halo C₁ -C₆alkoxy; carboxy; hydroxy(C₁ -C₆)alkyl C₂ -C₇ alkanoyloxy(C₁ -C₆)alkyl;(C₁ -C₆ alkoxy)carbonyl; amino including substituted amino, e.g mono- ordi- (C₁ -C₆ alkyl)-amino; nitro; hydroxy; mercapto; C₁ -C₆ alkylthio;(C₁ -C₆ alkyl)carbonyl; (C₆ -C₁₀ aryl)carbonyl; (C₂ -C₇)alkanoyloxy;(C7-C₁₁ )aroyloxy; (C₁ -C₆ alkyl)carbonylamino, (C₆ -C₁₀aryl)carbonylamino; (C₂ -C₇ alkoxycarbonyl)amino; C₆ -C₁₀ aryl;heteroaryl as defined above; or C₁ -C₂ alkylenedioxy; one of Y and Y₁ is##STR22## where R¹³ represents hydrogen, C₁ -C₆ alkyl or C₇ -C₁₆aralkyl; the other of Y and Y₁ is --CHR¹² -- where R¹² is hydrogen, C₁-C₆ alkyl or C₇ -C₁₆ aralkyl, or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier.